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74 Part II: The Organization of the Lymphohematopoietic Tissues Chapter 5: Structure of the Marrow and the Hematopoietic Microenvironment 75

mitochondrial apoptosis pathway in the homeostasis of the hematopoi- without the involvement of the hematopoietic cytokines. HSC and their
etic cells populations in the marrow. 583,584 Antiapoptotic members of the myeloid and lymphoid progeny have multiple toll-like receptors (TLRs)
Bcl-2 family (Bcl-2, Bcl-X , Mcl-1, and A1) stabilize the mitochondrial which bind specific bacterial or viral molecules. 596,597 The activation of
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membranes by preventing mitochondrial depolarization by the pore- TLRs leads to increased myelopoietic proliferation and differentiation,
585
forming family members, Bax and Bak. The antiapoptotic members especially of the monocyte/macrophage lineage, and differentiation
are also opposed by the proapoptotic, regulatory family members that of lymphoid cells toward the dendritic cell phenotype. 596,598 Although
consist of the BH3-only domain, such as Bim, Bid, Nix, and Puma. increased hematopoietic cytokines are produced by TLR activation, a
In HSC and multipotent progenitors, Mcl-1 is required to prevent direct response to TLR activation in hematopoietic cells changes the
apoptosis, and SCF stimulation increases the Mcl-1 expression. 586,587 prevalent myeloid transcription factor from C/EBPα, which mediates
In the later stages of single-lineage progenitors, Mcl-1 continues to be homeostasis by hematopoietic cytokines, to C/EBPβ, which mediates
required for survival of neutrophil and B and T lymphocytes, but it is the emergency responses to TLR activation. In response to the acti-
599
antagonized by the expression of Bim and Puma in these progenitors, vation of TLRs, mature neutrophils have decreased apoptosis as a result
providing a means to eliminate specific cells, such as autoreactive B and of increased Mcl-1 and decreased Bad activity. This may be a result
600
588
T lymphocytes. 583,584 A1 is required for normal neutrophil survival. of direct ligation of TLR receptors on LT-HSC, ST-HSC, and MPP that
In the erythroid lineage, Bcl-X is required to prevent apoptosis at are then stimulated to secrete cytokines such as IL-6, GM-CSF, and
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the late erythroblast stage, and the proapoptotic Nix protein is also TNF-α. 601,602 An alternative path to apoptosis in hematopoietic cells is
589
590
expressed. The sequential proapoptotic and antiapoptotic stimuli the activation of specific death-domain receptors for the ligands such as
that regulate erythropoiesis demonstrate overlapping and cooperative FAS ligand, TNF-α, and TRAIL (tumor necrosis factor–related apopto-
interactions that affect erythroid cell homeostasis by both survival and sis-inducing ligand). Although these ligands are most commonly asso-
differentiation. Following moderate blood loss, an increased percent- ciated with pathologic states where they may play a role in the anemias
552
age of HSC enter cell cycle and self-renewal. In the BFU-E through of chronic disease, they have also been proposed to have a regulatory
CFU-E stages, SCF and glucocorticoids act in concert to upregulate role in normal erythropoiesis. 603
proliferation according to the erythropoietic requirements. How-
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